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Vaccine of hepatitis E virus

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  • Assembly of virions begins with the production of capsid monomers (with or without an N-terminal region), which self-assemble into dimers and subsequently decamers. Decamers lacking the capsid N-terminal assemble into small virus like particles that are the source of HEV vaccines and serologic reagents. Decamers of full-length capsid monomers encapsidate the viral RNA to form full-size virions.
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    • 1. Vaccine of hepatitis E virus Samir Haffar M.D.
    • 2. Why we need a vaccine for hepatitis E virus?
    • 3. Global Burden of HEV Genotypes 1 and 2 in 2005 • Methods Annual disease burden of G1 & 2 for 9 of 21 regions Represent 71% of world’s population Defined for Global Burden of Diseases, Injuries, and Risk Factors Study (the GBD 2010 Study) • Results Incident 20.1 million 95% Cr.I.: 2.8-37.0 Symptomatic3.4 milliom 95% CrI: 0.5-6.5 Death 70.000 95% CrI: 12,400-132,732 Stillbirths 3.000 95% CrI: 1,892 – 4,424 CrI: Credible Interval Rein DB et al. Hepatology 2012 ; 55 : 988 – 997.
    • 4. • Incubation period 3 – 8 weeks • Prodromal phase Short • Symptoms or jaundice Days to several weeks • Most cases are self-limited • Case fatality rate 0 – 10% 20% in pregnant women Hoofnagle JH et al. N Engl J Med 2012 ; 367 : 1237 – 44 . Clinical features of hepatitis E Most HEV infections have clinically silent course
    • 5. • Inapparent or asymptomatic infection • Anicteric hepatitis Biochemical abnormalities – No jaundice • Icteric hepatitis Similar to other forms of viral hepatitis • Severe hepatitis Leading to fulminant hepatic failure • Acute-on-chronic liver disease Clinical features of hepatitis E Hepatic manifestations (common) Aggarwal R & Shahid J. Hepatology 2011 ; 54 : 2218 – 2226.
    • 6. • Acute pancreatitis • Hematological manifestations Thrombocytopenia, hemolysis • Autoimmune phenomena Membranous glomerulonephritis Henoch-Schonlein purpura • Neurological syndromes Guillian-Barre syndrome Meningoencephalitis Pseudotumor cerebri Cranial nerve palsies Bilateral pyramidal syndrome Peripheral neuropathy Extra-hepatic manifestations (Rare) Aggarwal R & Shahid J. Hepatology 2011 ; 54 : 2218 – 2226. Mostly as case reports or small case series Based usually on detection of anti-HEV IgM rather than HEV RNA
    • 7. Serological diagnosis of Hepatitis E Zakim & Boyer hepatology 2012 – 6th edition.
    • 8. Chronic hepatitis E Previously believed to be always self-limited • First reported in 2008 in 8 French solid organ transplant recipients receiving immunosuppressive drugs, & recently developed transaminase elevation, and had infection with genotype 3 • Also been reported in HIV infection, hematological diseases, or those receiving anticancer chemotherapy • Liver histology shows portal hepatitis with lymphocytic infiltrate, piecemeal necrosis & fibrosis; and in some cases, liver fibrosis • Persistent infection not reported with genotype 1 or 2 HEV, among otherwise healthy persons, or from highly endemic regions Kamar N et al. N Engl J Med 2008 ; 358 : 811 - 817.
    • 9. Course of HEV infection Wedemeyer H et al. Gastroenterology 2012 ; 142 : 1388 – 1397.
    • 10. Genotypes of HEV • HEV is classified into four major genotypes • All four genotypes are believed to represent a single serotype which has facilitated efforts to develop hepatitis E vaccines
    • 11. HEV infections according to genotype Characteristic Genotypes 1 and 2 Epidemic Genotypes 3 and 4 Autochthonous Distribution Developing countries Developing & developed countries Pattern of spread Epidemic & sporadic Sporadic Species Human Swine, human Mode of spread Waterborne Foodborne Icteric illness High Low Age Adolescents & young older Sex M = W Higher in men Mortality High in pregnancy High in older Extra-hepatic features Few Neurologic Chronic infection None In immunosuppressed patients Therapy None known Ribavirin, PEG-IFN Prevention Vaccine Vaccine Hoofnagle JH et al. N Engl J Med 2012 ; 367 : 1237 – 44 .
    • 12. Worldwide prevalence of HEV Endemic regions of hepatitis E where >25% of acute viral hepatitis is due to HEV Wedemeyer H et al. Gastroenterology 2012 ; 142 : 1388 – 1397.
    • 13. Geographic distribution of different HEV genotypes Wedemeyer H et al. Gastroenterology 2012 ; 142 : 1388 – 1397.
    • 14. Hepatitis E virus
    • 15. Genomic organization of HEV Zakim & Boyer hepatology 2012 – 6th edition. Short untranslated regions (UTR) at both ends Three open reading frames (ORFs) ORF1: encodes nonstructural polyprotein (nsp) ORF2: encodes the viral capsid protein ORF3: encodes small regulatory phosphoprotein
    • 16. Assembly of HEV virions Hoofnagle JH et al. N Engl J Med 2012 ; 367 : 1237 – 44 .
    • 17. Open Reading Frame 2 (ORF-2) Encodes viral capsid protein N-terminal signal sequence (SS) Domain 1: RNA encapsidation Domain 2: form core of viral capsid Domain 3: exposed on virus particle Neutralization epitope (aa 458 – 607) in domain 3 Binding of HEV to its cellular receptor Aggarwal R & Jameel S. Hepatol Int 2008 ; 2 : 308 – 315.
    • 18. ORF-2 & HEV vaccine • Antibody elicited in humans & animals against ORF2 is long lived, cross-reactive among diverse HEV genotypes & neutralizes HEV in vitro • ORF2 protein of HEV has been the antigen used for all vaccine studies thus far • Full-length or truncated forms of the protein expressed in bacterial cells, insect cells, yeast, animal & plant cells have emerged as potential vaccine candidates Kamili S. Virus Research 2011 ; 161: 93 – 100.
    • 19. Vaccine candidates for HEV Kamili S. Virus Research 2011 ; 161: 93 – 100. Light colored vertical bar indicates location of neutralizing epitope Blue bars indicate proteins undergoing clinical evaluation
    • 20. Preclinical & clinical studies of HEV
    • 21. Pre-clinical evaluation of HEV vaccine candidates ORF-2 protein Amino acids Source Remarks Expressed in E. coli TrpE-C2 221 – 660 Burma pE2 394 – 607 China HEV 239 368 – 606 China Human CT Expressed in insect Baculovirus-mediated Spodoptera litura larvae 56-kDa protein 53-kDa protein 62-kDa 50 kDa (VLPs) 62-kDa 112 – 607 112 – 577 112 – 660 112 – 534 112 – 660 Pakistan Burma Burma Burma India Human CT Oral route Expressed in other system Yeast Pichia pastoris Transgenic tomato plants HBV/HEV pE2 551 – 607 394 – 607 China China DNA vaccines Naked DNA plus protein pJHEV pcHEVORF2 +26 kDa 1 – 660 1 – 660 Burma Burma India Stability Easy preparation VLPs: Virus Like Particles
    • 22. 56 kDa vaccine Phase II – Double-blinded placebo-controlled RCT ShresthaMP et al. N Engl J Med 2007 ; 356 : 895 – 903. • 1 794 healthy subjects mostly male (99%) & young (mean 25y) • Compagny: GlaxoSmithKline Biologicals with the US army – Nepal • Randomization: HEV vaccine versus placebo • Primary end-point: prevention of clinically overt HEV infection • Predominantly if not exclusively genotype 1 • 20 μg IM at 0, 1, 6 months • Follow-up period: 2 years post-vaccination • Efficacy after third dose: 95,5% • Side effects: increased injection-site pain
    • 23. Limitation of 56 kDa vaccine • Study subjects mostly men (>99%) & young (mean age 25 years) • Primary end point was clinically overt HEV infection authors and did not study the HEV infection rate • anti-HEV antibody titers declined significantly by end of the study, so that nearly 44% of subjects had antibody titers below the level considered as protective
    • 24. 56 kDa vaccine • GlaxoSmithKline did not pursue the manufacture of this vaccine despite its efficacy • The firm estimates that there is little commercial potential for the vaccine
    • 25. Regulatory milestones of HEV 239 vaccine • 2001 Researchers at Xiamen University modified a E. coli strain to produce protein stimulating immune system in humans, to make protective antibodies against HEV • 2000 Yangshengtang Group joint biotech laboratory with the university & preclinical/clinical development began • 2006 Laboratory given national status by Chinese Ministry of Science and Technology & relaunched as NIDVD* • 2007 Yangshengtang set up subsidiary company (Innovax) to take potential vaccines from CT to manufacturing • 2010 Publication of phase III trial of HEV 239 in Lancet • 2011 Vaccine approved by China FDA * NIDVD: National Institute of Diagnostics and Vaccine Development in Infectious Diseases Human Vaccines Immunotherapeutics 2012 ; 8 : 1743 – 1744.
    • 26. Clinical milestones of HEV 239 vaccine All studies conducted in China during 2005 – 2009 Phase I 2005 Safety – Guangxi province – 44 volunteers of ages 21-55 20 μg HEV vaccine at 0 – 1 month Phase IIa Dose schedule & dose escalation – 457 subjects 2 schedules: 0 – 6 & 0 – 1 – 6 mo anti-HEV IgG seroconversion higher in 3-dose group Difference not statistically significant (100% vs. 98%) GMC of anti-HEV IgG significantly higher in 3-dose group Phase IIb 155 subjects – 4 groups – 3 doses of 10, 20, 30, 40 μg 100% seroconversion in all four groups High-dosage groups (20, 30 & 40 μg) showed higher anti-HEV IgG GMC levels than 10-μg dosage group AE similar among four dosage groups Phase III 2007 – 2009 Large scale double blind placebo-controlled RCT Zhang J et al. Vaccine 2009 ; 27 : 1869 – 74.
    • 27. HEV 239 vaccine – Hecolin® Phase III – Double blind placebo-controlled RCT • 112 604 healthy subjects, men & women, 16 – 65 years • Compagny: Xiamen Innovax Biotech – China • Randomization: HEV vaccine versus HBV vaccine • Primary end-point: prevention of clinically overt HEV infection • Genotype 1 & 4 prevalent – Predominant genotype 4 • 30 μg IM at 0, 1, 6 months • Follow-up period: 13 month post-vaccination • Efficacy after third dose: 100% • No side effects Zhu FC et al. Lancet 2010 ; 376 : 895 – 902.
    • 28. In December 2011, the China Food & Drug Administration approved the hepatitis E vaccine Hecolin® for use in subjects ≥ 16 year old
    • 29. Who should get the vaccine? • Travelers to endemic areas • Pregnant women in endemic areas • Food industry workers • Aged persons • During HEV outbreaks (100% efficacy after 2 doses/1mo) • Organ transplantation receptors • Patients with underlying chronic liver disease High risk groups Wu T et al. Human Vaccines & Immunotherapeutics 2012 ; 8 : 823 – 827.
    • 30. Questions remain to be answered • HEV infection rate (focus was on clinical disease rate) • Titer of protective antibodies • Duration of protection afforded by the vaccine • Used for post-exposure prophylaxis • Safety in Pregnant women People younger than 15 y or older than 65 y Chronic liver disease Immunosuppressed patients
    • 31. Safety of Hecolin® in pregnant women Post-hoc analysis • Safety of the vaccine for pregnant women was demonstrated by preliminary analysis in 37 pregnant women who inadvertently received 1, 2 or 3 doses of HE vaccine during pregnancy • The vaccine was well tolerated The babies born in the vaccine group were as healthy as those born in the control group Wu T et al. Hepatology 2012 ; 55 : 2038.
    • 32. Financial aspects of Hecolin® • Development of Hecolin® cost about 500 million renminbi or $80 million, much of which came from Chinese government through the university • The vaccine will be sold to distributors in China at cost of 110 renminbi ($17.60) per dose • Innovax expects sales to reach 62 million renminbi in 2013 Human Vaccines Immunotherapeutics 2012 ; 8 : 1743 – 1744.
    • 33. Xiamen University and Innovax are in talks with the World Health Organization (WHO) to register Hecolin with the organization’s Prequalification Programme, which makes medicines available to agencies such as: • the United Nations Children’s Fund • the Joint UN Programme on HIV/AIDS Park SB. Nature 2012 ; 491 : 21 – 22.
    • 34. Jeremy Farrar Director of Oxford University Clinical Research Unit “New companies operating with different funding models offer a great opportunity, & one which could have a profound impact.” “We have to be sure that these vaccines can be used anywhere” “It would be a great shame if these products were not available outside China” Park SB. Nature 2012 ; 491 : 21 – 22.
    • 35. Conclusion Though several questions remain to be answered, the successful clinical testing of this vaccine is a major step forward in the future control of HEV
    • 36. Thank You